Our earlier work defined and characterized the ability of glucagon, catecholamines, and insulin to regulate the increase in hepatic glucose production and the ability of insulin and catecholamines to control glucose utilization during exercise. The aim of the studies in this proposal is to study the means by which substrate availability may influence hepatic and muscle carbohydrate metabolism during exercise, independent of changes in hormone levels. Specifically, we will study the means by which glucose, free fatty acids (FFAs), and O2 availability affect hepatic and muscle carbohydrate metabolism. Studies will be conducted during rest and treadmill exercise in overnight-fasted dogs in which hormone levels and neural outflow will be controlled using surgical (pancreatectomy, denervation, adrenalectomy) and pharmacological (somatostatin) methods. Hepatic glycogenolysis and gluconeogenesis and muscle glycogenolysis, glucose uptake, and glucose metabolism will be assessed using arteriovenous differences and tracer techniques. It is a goal of the proposed experiments to isolate the direct effects of changes in glucose, FFAs, and O2 availability from the effects which may be mediated by the endocrine and nervous systems. In the first set of experiments we will study the effects of altering glucose load on liver and muscle carbohydrate metabolism during exercise. The dynamics of insulin-independent glucose uptake and metabolism by the working muscle will be determined by varying the circulating glucose level in the presence of a fixed insulin concentration. In addition, the ability of a glucose load to modulate the exercise-induced rise in hepatic glycogenolysis and gluconeogenesis will be assessed. The second group of studies is designed to elucidate the impact of altering fat availability on hepatic and muscle carbohydrate metabolism during exercise in normal and insulin-deficient states. Moreover, we will determine the role of FFAs in mediating hormone action on glucose metabolism. In the third set of experiments the metabolic effects of the diminished O2 availability resulting from anemia will be determined. The aim of these studies will be to elucidate the mechanism by which a decrease in O2 availability increases the reliance of the working muscle on carbohydrates as a fuel. An effort will be made in these studies to differentiate between the direct effects of a diminished O2 availability and those effects which are mediated by the endocrine system. These studies should further our understanding of the factors which regulate carbohydrate metabolism in the liver and working muscle under physiologic conditions and under pathologic conditions in which the circulating levels of glucose, FFA, and O2 may be altered.